The effect of maternal metabolic status on offspring health: a role for skeletal muscle?

Metabolic health is determined by genetic and behavioural factors, including but not limited to diet and exercise. The metabolic status of the mother before and during gestation and lactation influences an individual's predisposition to chronic disease. Growing evidence supports that fetal development, from conception to infancy, is a highly plastic process. The quality of the intra‐uterine environment depends on maternal metabolic health and plays an important role in fetal tissue and organ development. A suboptimal intra‐uterine environment alters offspring metabolism and cell function. This effect can translate into adulthood, increasing susceptibility to non‐communicable diseases later in life. The phenomenon can even endure into future generations, a process known as transgenerational epigenetic inheritance (Heindel & Vandenberg, 2015). These concepts form the basis of the Developmental Origins of Health and Disease (DOHaD) theory.

Maintaining optimal skeletal muscle mass and function over the lifespan is essential in preventing the development of chronic diseases (Bayol et al. 2014). Skeletal muscle is a key metabolic tissue, accounting for 20–30% of whole‐body energy expenditure at rest and up to 90% during exercise. Following a meal, about half of glucose disposal relies on skeletal muscle. Muscle mass and metabolism are therefore primary determinants of metabolic disorders including type 2 diabetes, cardiovascular disease and obesity. Other muscle functions include mobility, thermogenesis and nutrient storage in the form of fat, glycogen and amino acids. Nutrient storage is particularly important during periods of chronic stress, such as advanced disease progression or starvation. During these occurrences, the preservation of other organs, such as the liver and brain, is prioritized and maintained through acquiring amino acids from skeletal muscle. This results in muscle mass loss, impaired metabolic function and higher incidence of secondary diseases. Despite the major contribution of skeletal muscle to whole‐body metabolism, its role in preventing disease progression has often been undervalued (Wolfe, 2006).

Skeletal muscle mass throughout adulthood is largely determined by its development in utero (Bayol et al. 2014). Skeletal muscle fibres are postmitotic cells that rely on optimal prenatal muscle development to achieve adequate muscle mass in adulthood. Postnatal muscle growth is driven by increases in the size of muscle fibres rather than increases in fibre number, which is established at birth. Maternal diet and exercise status can affect offspring skeletal muscle development. The DOHaD theory was initially formulated from studies based on maternal undernutrition in humans. Offspring born to underfed mothers were typically born small for gestational age and were at increased risk of developing hypertension and obesity in adulthood. More recently, increases in global obesity rates and excessive gestational weight gain saw a shift in research focus to maternal overnutrition. Offspring born to mothers consuming an obesogenic diet are typically greater in body weight. However, animal models have shown that both resulted in lower muscle fibre numbers and muscle quality. This impaired muscle development in the offspring may translate into an increased risk of developing chronic disease in adulthood.

Maternal activity status is less well characterized, but studies focusing on the effects of maternal training on offspring metabolism have begun to emerge. A previous study from Quiclet and colleagues showed that maternal training in rats improved short‐term male offspring pancreatic function and insulin secretory capacity (Quiclet et al. 2016). However, these effects were not maintained later in life. Despite no reduction in overall insulin sensitivity, 7‐month‐old offspring from trained dams tended to have altered glucose tolerance, decreased islet insulin secretory capacity and decreased insulin sensitivity in the muscle when compared to their control counterparts. In contrast, maternal exercise improved glucose tolerance in female offspring over a 52‐week period, regardless of maternal diet (Stanford et al. 2017).

In a recent study in The Journal of Physiology, Quiclet et al. (2017) used female Wistar rats that underwent 4 weeks of continuous submaximal physical exercise prior to mating. Exercise was maintained during gestation and ceased post‐partum. Control groups remained sedentary in their home cages. Post‐weaning, offspring were placed on either a standard chow diet comprising 5.1% fat and 4.4% total sugar or a high‐fat/high‐sucrose diet comprising 36% fat and 16.6% sucrose for 10 weeks post‐weaning. Training had no effect on maternal body weight or food consumption. However, pups born to trained mothers had lower body weights 7 and 21 days post‐partum when compared to pups born to sedentary mothers. Despite greater caloric intake and greater weight gain in pups fed a high‐fat/high‐sucrose diet when compared with control pups, bodyweight at the end of the experiment remained significantly lower in offspring born to trained dams in both diet groups. In addition, maternal training protected offspring fed a high‐fat/high‐sucrose diet from gaining excessive fat mass. The cause of these positive effects, however, remains partly unclear and may be credited to several factors, including but not restricted to enhanced pancreatic function, improved glucose utilization from the liver or the muscles and a shift in muscle substrate utilization.

Maternal training before and during gestation improved the offspring's energy substrate handling in early adulthood. It was proposed that some of these positive effects are due to changes in substrate metabolism in skeletal muscle. Skeletal muscle mass did not vary with maternal training status or diet. However, maternal training increased markers of insulin sensitivity in the gastrocnemius muscle of both diet groups. In the plantaris muscle, it also facilitated access of products of glycolysis (pyruvate) and the Krebs cycle (palmitoyl‐CoA) to the electron transport chain, despite no changes in markers of mitochondrial activity. The authors not only suggest that their results point towards an increased mitochondrial affinity for lipid substrates, but also speculate that this may constitute a mechanism preventing fat mass gain by reducing intramuscular lipid storage opportunities. Of particular interest for human health in the context of epidemic obesity, this muscle‐specific effect disappeared when offspring received a high‐fat/high‐sucrose diet.

Overall, Quiclet et al. report that maternal training benefited substrate handling in the offspring, but was only partly protective when the offspring consumed a high fat/high sucrose diet. Whereas maternal training had a positive effect on whole‐body fat mass regardless of diet, skeletal muscle, along with other tissues including the liver and the pancreas, was susceptible to both maternal training and diet. These results reflect the plasticity of skeletal muscle, a tissue that retains its potential to positively or negatively adapt across the lifespan. In adulthood, factors such as diet and exercise directly influence skeletal muscle mass and quality through their effect on substrate metabolism and muscle protein turnover. Active individuals consuming a balanced diet maintain lean muscle mass and proper metabolic function, which are essential for preventing obesity and offsetting age‐related muscle mass loss or sarcopenia. In contrast, excessive caloric intake and sedentary lifestyles result in fat accumulation and ectopic fat deposition in non‐adipose tissues including skeletal muscle (Bayol et al. 2014). Intramuscular fat deposition is favourable for trained athletes as it provides a fuel source for activity. However, muscles of sedentary individuals are ill equipped to utilize these fat deposits. Over time, this intramuscular fat content disturbs the insulin signalling pathway, resulting in insulin resistance and impaired glucose handling (Bayol et al. 2014). Muscle disorders are exacerbated with advancing age, where the elderly commonly experience ‘sarcopenic obesity’, a decrease in muscle mass that is associated to excessive weight gain (Wolfe, 2006). As sarcopenia progresses, individuals become frail and rates of hospitalizations increase, resulting in exacerbated muscle mass loss from bed‐rest and decreased quality of life.

Only males were investigated in Quiclet's study. The influence of a maternal diet on offspring muscle metabolism is sex‐specific, and studies have reported sex differences in serum glucose and insulin profiles when the mother and offspring consumed a ‘junk food’ diet. The effect of maternal training on offspring metabolism in a sex‐specific manner is not as well documented. A study by Stanford et al. (2017) showed that both female and male offspring responded to maternal exercise during gestation, which negated the effects of a maternal high‐fat diet on glucose tolerance. However, the magnitude of these changes significantly varied between males and females, confirming the need to further explore sex‐specific differences in the way maternal exercise protects offspring from metabolic dysfunction.

Studies reporting the deleterious effects of a suboptimal maternal diet and sedentary lifestyle on long‐term offspring muscle metabolism support the long‐known need for implementing maternal lifestyle interventions to optimize offspring development. Overall, this study suggests that exercise interventions are essential but not sufficient to provide protection to the offspring's muscle against an obesogenic diet. This highlights that whilst positive maternal behaviour is critical for offspring optimal skeletal muscle development, skeletal muscle remains vulnerable to diet and exercise later in life.